Histone modification of endothelial-mesenchymal transition in cardiovascular diseases

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  FIGURE 1. Influencing factors and canonical signaling pathways of endothelial-mesenchymal transition. Transforming growth factor-β (TGF-β) signal is initiated, type II receptor activates type I receptor ALK1, phosphorylates Smad2/3, and the latter combines with Smad4 to form a complex into the nucleus to activate transcription factors Snail, Twist1, Slug et al., promoting EndMT; While the type II receptor activates the type I receptor ALK5 and inhibits EndMT via Smad1/5; Smad6/7 also inhibits EndMT by Smad2/3; The non-Smad pathways activated by TGF-β include: PI3K/Akt, Rho GTPase, etc. Other pathways that activate EndMT: Wnt/β-catenin and Notch signaling pathways. High glucose, hypoxia, oxidative stress, and shear stress can all activate the EndMT process through various mechanisms. EndMT manifests as loss of endothelial markers: Vascular endothelial cell-cadherin, VE-cadherin, Platelet endothelial cell adhesion molecule-1, CD31/PECAM, von Willebrand Factor, vWF, endothelial Nitric Oxide Synthase, eNOS, Vascular endothelial growth factor receptor, VEGFR; Obtainment of mesenchymal markers: Actin alpha 2,α-SMA/ACTA2, Smooth muscle 22α, SM22α, Vimentin, Fibronectin, FN/FN-EDA,…

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  FIGURE 2. Regulation of EndMT by histone methylation and demethylation. TGF-β promotes fibrosis, inflammation, shear stress, hypoxia and other EndMT environments, up-regulates JMJD2B expression, demethylates histone H3K9me3, activates target genes Calpoin1, Vimentin, SULF1, and promotes EndMT process; EndMT stimulators activate E2H2, methylate histone H3K27me3, inhibit the expression of target gene α-SMA, and inhibit the EndMT process.

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  FIGURE 3. Epigenetic regulation of histone acetylation and deacetylation in cardiovascular disease. (A) Histone acetyltransferases (HATs) relax packaged chromatin to promote gene transcription, and histone deacetylases (HDACs) promote chromatin packaging to inhibit gene transcription. The HDACs family is divided into zinc lipoprotein dependent and NAD + dependent, Zinc lipoprotein dependent enzymes include: class I: HDAC1, 2, 3, 8, which are mainly expressed in the nucleus; class II: IIa: HDAC4, 5, 7, 9; IIb: HDAC6, 10, which are expressed in both the nucleus, nucleus, and cytoplasm; class IV: HDAC11. NAD + dependent enzymes include: Class III: SIRTs1-7. (B) After the heart is pathologically stimulated, HDACs can activate an inflammatory response and oxidative stress, promote fibrosis, damage endothelial cell barrier function, and promote endothelial cell senescence and EndMT process leading to cardiovascular diseases such as atherosclerosis, myocardial fiber Cardiac hypertrophy, hypertension, etc. At the same time, HDACI Can antagonize the adverse effects of HDACs.